Synthesis of functionalized 1,2-dihydropyridines bearing quaternary carbon centers via an organocatalytic allylic alkylation

Tetrahedron Letters 56 (2015) 937–940

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Synthesis of functionalized 1,2-dihydropyridines bearing quaternary carbon centers via an organocatalytic allylic alkylation Gong-Feng Zou, Zhi-Peng Hu, Shi-Qiang Zhang, Wei-Wei Liao ⇑ Department of Organic Chemistry, College of Chemistry, Jilin University, Changchun 130012, PR China

a r t i c l e

i n f o

Article history: Received 18 November 2014 Revised 15 December 2014 Accepted 21 December 2014 Available online 7 January 2015

a b s t r a c t The first tertiary amine-catalyzed allylic alkylation of Reissert products of pyridine derivatives has been demonstrated. This protocol provided an efficient synthetic route for the construction of functionalized 2,2-disubstituted 1,2-dihydropyridines incorporating quaternary carbon centers with good to high regioselectivities and moderate enantioselectivities. Ó 2014 Elsevier Ltd. All rights reserved.

Keywords: Organocatalysis Dihydropyridine Allylic alkylation Asymmetric catalysis

The syntheses of functionalized 1,2-dihydropyridines have received considerable attention due to their importance in organic synthesis and medicinal chemistry.1 For example, 1,2-dihydropyridines are important building blocks in the preparation of piperidine scaffolds which are valuable and prevalent heterocyclic structural units in biologically active compounds and in medicines which have been enormously important in treating diseases.2 Although a number of synthetic methods have been developed to construct these valuable structural motifs,1,3 few examples have been demonstrated to prepare the functionalized 1,2-dihydropyridines incorporating quaternary carbon centers.4,5 Reissert reaction of pyridine derivatives has been well known to construct a-cyano substituted 1,2-dihydropyridines which can be regarded as cyclic a-aminonitriles for several decades.6 In contrast to other a-aminonitriles bearing a a-hydrogen which are exceptionally versatile intermediates in synthetic chemistry and have been widely used in the generation of multiple polyfunctional structures,7 the synthetic applications of dihydropyridines derived from Reissert reaction of pyridine derivatives have received less attention.1a With the goal of developing efficient metal-free processes to construct the diverse carbon frameworks incorporating quaternary carbon centers,8 herein we report a facile approach to prepare 2,2-disubstituted functionalized dihydropyridines bearing quaternary carbon centers from Reissert products of pyridine derivatives by using a Lewis base assisted Brønsted base catalyzed

⇑ Corresponding author. E-mail address: [email protected] (W.-W. Liao). http://dx.doi.org/10.1016/j.tetlet.2014.12.116 0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

R1

R1 OBoc

O

CO2R

CN

N R2 1

2

LB (cat.) N CN COR2

CO2R

3

Scheme 1. Synthetic strategy on preparation of 2,2-disubstituted functionalized dihydropyridines. LB = Lewis base.

allylic alkylation,9 which takes advantage of the powerful anionstabilizing capacity of the cyano-group (Scheme 1). Our initial investigation commenced with Morita–Baylis–Hillman (MBH) adduct 2 and ethyl 2-cyano-5-(diisopropylcarbamoyl) pyridine-1(2H)-carboxylate 1aa which are readily prepared from Reissert reaction of nicotinic amide. In the presence of catalytic amount of DABCO (20 mol %), the reaction provided the desired a-selective alkylation product 3a along with the small amount of c-regioisomer 4aa in CH3CN (Table 1, entry 1). Other tertiary amine catalysts such as DMAP and DBU have been examined, and the reactions afforded the desired product 3aa in reduced yields (Table 1, entries 2–3). Similar to DMAP and DBU, treatment of 1aa and 2 with PPh3 (10 mol %) gave alkylation product 3aa in moderate yield and regioisomer 4aa in 16% yield (Table 1, entry 4). Further screening on solvents showed that the a-selective allylic alkylation reaction proceeded well in more polar solvent and gave the desired product 3aa in good yields (Table 1, entries 1 and 8), while the moderate yields were obtained in the presence of less polar solvents due to the increased production of regioisomer 4aa (Table 1, entries 5–7).

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Table 1 Optimization of allylic alkylation of compound 1a with MBH carbonate 2a

R1

OBoc CO2Me N CN CO2Et 1aa

cat.(20 mol%)

R1

solvent

CO2Me CN CO2Et

2

CO2Me

R1

+

N

Table 3 Allylic alkylation of MBH adduct 2 with 1,2-dihydropyridines 1 with substituents at the 4 or 3-positiona

4

R1

3

OBoc

2

N CN CO2Et 4aa

3aa

R1

N1 O

R1 = CONiPr2

CO2Me

CN

R2 1

DABCO (20 mol%) N CN COR2

CH3CN, rt

CO2Me

+

3

2

CO2Me

R1

CN N CO2Et 4

Entry

Cat.

Solvent

Yieldb (%)

3aa/4aac

Entry

R1

R2

1

t (h)

Yieldb (%)

3/4c

1 2 3 4 5 6 7 8

DABCO DMAP DBU PPh3 DABCO DABCO DABCO DABCO

CH3CN CH3CN CH3CN CH3CN PhCH3 DCM THF DMF

82 61 50 50 62 66 66 77

9.1:1 10:1 5.6:1 3.1:1 2/1 2/1 2.8/1 7/1

1 2 3 4e 5 6 7 8 9 10e 11 12e 13f 14f 15e 16 17 18 19 20

(4-)CON(Et)2 (3-)CON(Et)2 (4-)CON(OMe)Me (3-)CON(OMe)Me (4-)CON(iPr)2 (3-)CON(iPr)2 (4-)CON(CH2)4O (3-)CON(CH2)4O (4-)CON(CH2)5 (3-)CON(CH2)5 (4-)CO2Me (3-)CO2Me (4-)CN (3-)CN (4-)Cl (3-)Cl (4-)CO2Me (3-)CO2Me (4-)CO2Me (3-)CO2Me

OEt OEt OEt OEt OEt OEt OEt OEt OEt OEt OEt OEt OEt OEt OEt OEt Me Me Ph Ph

1ba 1ca 1bb 1cb 1bc 1cc 1bd 1cd 1be 1ce 1bf 1cf 1bg 1cg 1bh 1ch 1bi 1ci 1bj 1cj

13 39 13 24 11 24 3 24 3 24 24 22 4 5 24 5 24 23 24 24

66 59 70 63 66 nr 54 60 66 57 nr 48 28 97 77 76 nr 66 nr 75

2.3/1 —d 5.3/1 —d 3.7/1 —d 1.9/1 —d 2.7/1 —d

a Reactions were performed with 1aa (0.2 mmol), 2 (0.26 mmol), and catalyst (20 mol %) at 30 °C in solvent (c = 0.2 M). b Yield of isolated product 3aa. c Based on 1H NMR analysis.

With these optimized reaction conditions in hand, allylic alkylation reactions between 1,2-dihydropyridines 1 bearing various substituents at the 5-postion with MBH adduct 2 were evaluated firstly (Table 2). The substrates with amide moieties as electronwithdrawing groups (EWG) were well tolerant. The range of nicotinic amide Reissert compounds furnished the desired 2,2-disubstituted dihydropyridines 3 in good to high yields with moderate to high regioselectivities (Table 2, entries 1-5). Notably, substrate 1ac including the Weinreb amide moiety was a suitable substrate and gave the desired product 3ac in good yield with good regioselectivity (Table 1, entry 3), which enabled the further elaborate synthetic transformation. In addition, substrates with substituents such as cyano and ester at the 5-postion also gave the a-selective alkylation products 3 in good yields (Table 2, entries 6–7). NSubstituents on 1,2-dihydropyridines 1 were examined. N-Isobutyloxy

Table 2 Allylic alkylation of MBH adduct 2 with 1,2-dihydropyridines 1 with substituents at 5-positiona CO2Me R1

OBoc CO2Me CN N COR2

DABCO (20 mol%)

R1

CH3CN, rt

CO2Me N CN COR2

2

1

R1 + NC

3

N COR2 4

Entry

R1

R2

1

Yieldb (%)

3/4c

1 2 3 4 5d 6d 7d,e 8 9 10 11

CON(iPr)2 CONEt2 CON(OMe)Me CON(CH2)5 CON(CH2)4O CO2Me CN CON(CH2)4O CON(CH2)4O CON(CH2)4O CO2Me

OEt OEt OEt OEt OEt OEt OEt Oi-Bu OBn OPh Me

1aa 1ab 1ac 1ad 1ae 1af 1ag 1ah 1ai 1ag 1ak

82 77 70 78 77 99 80 72 61 59 71

9.1/1 8.5/1 9/1 11/1 10/1 8/1 17/1 9/1 13/1 >19/1 2.7/1

(3aa) (3ab) (3ac) (3ad) (3ae) (3af) (3ag) (3ah) (3ai) (3aj) (3ak)

a Reactions were performed with 1 (0.2 mmol), 2 (0.26 mmol), and DABCO (20 mol %) at 30 °C in CH3CN (c = 0.2 M) for 1–5 h. b Yield of isolated product. c Determined by 1H NMR analysis. d Unseparated mixture was isolated. e 4 Å molecular sieve was added.

(3ba) (3ca) (3bb) (3cb) (3bc) (3bd) (3cd) (3be) (3ce) (3cf) (3bg) (3cg) (3bh) (3ch) (3ci) (3cj)

—d —d —d —d —d — —d — —d

a

Reactions were performed with 1 (0.2 mmol), 2a (0.26 mmol), and DABCO (20 mol %) at 30 °C in CH3CN (c = 0.2 M). b Yield of isolated product. c Determined by 1H NMR analysis. d No compound 4 was detected. e Performed at 60 °C. f 4 Å molecular sieve was added.

Reissert analogue 1ah gave the similar result as that of N-ethoxycarbonyl substituted 1,2-dihydropyridine 1aa (Table 2, entry 8), while N-benzyloxycarbonyl and N-phenyloxycarbonyl Reissert analogues provided the desired products 3ag–3ak in decreased yields with high regioselectivities (Table 2, entries 9–10). Besides, N-acetyl 1,2-dihydropyridine 1ak also served as suitable substrate and gave product 3ak in moderate yield with low regioselectivity (Table 2, entry 11). On the basis of these, the number of 1,2-dihydropyridines 1 with substituents at the 4- and 3-position were investigated, respectively. The results are illustrated in Table 3. In general, the reaction of substrate 1 with amide moiety at the 4-position proceeded faster than that of substrate 1 with amide moiety at the 3-position which required prolonged reaction time, presumably due to the steric hindrance effects of the R1 group at the 3-position. Treatment of 1,2-dihydropyridine 1cc with bulk substituent at the 3-position failed to give the desired product 3cc (Table 3, entry 6), while analogue 1bc with bulk substituent at the 4-position furnished the allylic alkylation product 3bc in moderate yield (Table 3, entry 5), which is consistent with aforementioned hypothesis. Substrates (1bb and 1cb) possessing Weinreb amide moieties can also be employed and gave the desired products in good yields irrespective of the substitution patterns (Table 3, entries 3–4). Further investigations on the reactions of substrates 1 bearing other electron-withdrawing groups (R1) revealed that the substitution patterns and the electronic properties (R1) have considerable influence on the chemical conversion and regioselectivity of the developed process. For examples, substrates (1cf and 1cg) with ester or cyano moieties (R1) at the 3-position provided the desired products in moderate to good yields (Table 3, entries 12 and 14), while corresponding 1,2-dihydropyridines (1bf and 1bg) with R1

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Figure 1. X-ray crystal structure of compound 3cf.

Table 4 Allylic alkylation of MBH adduct 2 with disubstituted 1,2-dihydropyridines 1a R2

N CN CO2Et

R2

R3

R1

R3

OBoc CO2Me

CN N CO2Et 1

Cl

R1

HO

m-CPBA o

CO2Me DCM, -10 C

m-ClC6H5OCO

3ch

DABCO (20 mol%) N CN CO2Et

CH3CN, 30 oC

2

Cl N CN CO2Et

CO2Me

5 (major) yield: 70%, dr = 2.3/1;

CO2Me

3

Entry

R1

R2

R3

1

t (h)

Yieldb (%)

1 2 3

H CN Cl

Ph Ph iPr

CN H H

1d 1e 1f

1 0.5 7

92 (3d) 95 (3e) 70 (3f)

a Reactions were performed with 1 (0.2 mmol), 2a (0.26 mmol), and DABCO (20 mol %) at 30 °C in CH3CN (c = 0.2 M). b Yield of isolated product.

Table 5 Catalytic asymmetric allylic alkylationa

R1

OBoc CO2Me N CN COR2

1 R1 = CON(CH2)4O;

R1 cat. (10 mol%) o CH3CN, 30 C

R1

CO2Me N CN COR2

2

R2

Cat.

Yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13

OEt OEt OEt OEt OEt OEt OEt OEt OEt OEt Oi-Bu OBn OPh

Quinidine Quinine Hydroquinidine Cinchonidine Cinchonine b-ICD (DHQD)2AQN (DHQ)2AQN (DHQD)2PHAL (DHQ)2PHAL Quinine Quinine Quinine

73 54 62 59 54 52 26 35 13 17 60 58 42

(3ae) (3ae) (3ae) (3ae) (3ae) (3ae) (3ae) (3ae) (3ae) (3ae) (3ah) (3ai) (3aj)

5 (major) N CN COR2 4

3

Entry

CO2Me

+

ee (%)c 32 45 26 30 24 29 5 5 5 27 28 46 58

Scheme 2. Synthetic application and X-ray crystal structure of compound 5 (major).

3/4d 10/1 11/1 12/1 10/1 10/1 12/1 11/1 12/1 9/1 11/1 12/1 14/1 >19/1

a Reactions were performed with 1 (0.1 mmol), 2a (0.13 mmol), and catalyst (10 mol %) at 30 °C in CH3CN (c = 0.2 M) for 48 h. b Yield of isolated product. c Determined by chiral HPLC analysis. d Determined by 1H NMR analysis.

groups at the 4-position gave few desired products (Table 3, entries 11 and 13). Notably, substrates with R1 groups at the 3-postion afforded the excellent regioselectivities, whereas the 4-postion

substituted analogues provided the moderate regioselectivities in general. However, the reactions of chloro substituted substrates (1bh and 1ch) proceeded well and gave the good yields with excellent regioselectivities, regardless of whether chlorine is located at the 3- or 4-position (Table 3, entries 15–16). Besides, the substitution patterns also affected the reactivity of the alkylation reactions between MBH adduct 2 with 1,2-dihydropyridines 1 bearing different N-substituents. N-Acetyl and N-benzoyl 1,2-dihydropyridines (1ci and 1cj) with EWG groups at the 3-position delivered the desired 2,2-disubstituted dihydropyridines 3 in moderate to good yields (Table 3, entries 18 and 20), while the corresponding 4-position substituted analogues (1bi and 1bj) did not provide any the desired allylic alkylation products (Table 3, entries 17 and 19). The structure of 3cf was further confirmed by X-ray analysis (Fig. 1).10 In addition, the allylic alkylation reactions of disubstituted Reissert analogues were evaluated (Table 4). To our delight, 3,4- or 4,5disubstitution patterns were tolerant and the reactions provided the multiple substituted 2,2-disubstituted dihydropyridines in good to high yields.

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Further investigation of asymmetric allylic alkylation reactions of MBH adduct 2 with 1,2-dihydropyridines 1 was carried out by employing various chiral tertiary amines and solvents (Table 5).11 Quinine gave the best enantioselectivity. (Table 5, entries 1–10). Asymmetric transformation of 1aa and 2 provided the moderate enantioselectivity (45% ee) (Table 5, entry 1). 1,2-Dihydropyridines with different N-substituents 1ah–1aj were employed under optimized reaction conditions (Table 5, entries 11–13). Among them, product 3ai was obtained in 42% yield with 58% ee (Table 5, entry 13).12,13 Finally, the synthetic utilities of allylic substituted 1,2-dihydropyridine were illustrated (Scheme 2). The treatment of compound 3ch with m-CPBA in CH2Cl2 afforded cis-6-(3-chlorobenzoyloxy)-5hydroxy-5, 6-dihydropyridine 5 in 70% yield, which may proceed through the initial epoxidation of the unsubstituted enamine double bond followed by cis-ring opening in situ by m-CPBA regio- and stereoselectively, due to the steric hinderance effect of the neighboring allylic group. The structure of major product 5 was confirmed by X-ray analysis.10 In conclusion, we have developed a tertiary amine-catalyzed allylic alkylation reaction between Reissert products of pyridine derivatives and MBH adduct. This method provided a facile synthetic route for the preparation of functionalized 2,2-disubstituted 1,2-dihydropyridines incorporating quaternary carbon centers with good to high regioselectivities and moderate enantioselectivities. In addition, the synthetic application of the functionalized 1,2-dihydropyridine product was also demonstrated. Further studies on synthetic transformations are ongoing in our laboratory. Acknowledgments W.-W. Liao thanks NSFC (No. 21372096) for financial support. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.12. 116. References and notes 1. For reviews on the synthesis and applications of 1,2 dihydropyridines, see: (a) Silva, E. M. P.; Varandas, P. A. M. M.; Silva, A. M. S. Synthesis 2013, 3053; (b) Comins, D. L.; Higuchi, K.; Young, D. W. Adv. Heterocycl. Chem. 2013, 110, 175; (c) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B. Chem. Rev. 2012, 112, 2642; (d) Lavilla, R. J. Chem. Soc., Perkin Trans. 1 2002, 1141; (e) Kuthan, J.; Kurfürst, A. Ind. Eng. Chem. Prod. Res. Dev. 1982, 21, 191.

2. For an analysis of the prevalence of piperidines in drugs, see: (a) Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451; (b) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52, 6752; (c) Walters, W. P.; Green, J.; Weiss, J. R.; Murcko, M. A. J. Med. Chem. 2011, 54, 6405; (d) Ritchie, T. J.; Macdonald, S. J. F. Drug Discov. Today 2009, 14, 1011; For general reviews on piperidines, see: (e) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139; (f) Buffat, M. G. P. Tetrahedron 2004, 60, 1701; (g) Mitchinson, A.; Nadin, A. J. Chem. Soc. Perkin Trans. 1 2000, 2862; (h) Laschat, S.; Dickner, T. Synthesis 2000, 1781. 3. For recent methods for the synthesis of 1,2-dihydropyridines, see: (a) Mizoguchi, H.; Oikawa, H.; Oguri, H. Nat. Chem. 2014, 6, 57; (b) Chau, S. T.; Lutz, J. P.; Wu, K.; Doyle, A. G. Angew. Chem., Int. Ed. 2013, 52, 9153; (c) Yamakawa, T.; Yoshikai, N. Org. Lett. 2013, 15, 196; (d) Oshima, K.; Ohmura, T.; Suginome, M. J. Am. Chem. Soc. 2012, 134, 3699; (e) Amatore, M.; Leboeuf, D.; Malacria, M.; Gandon, V.; Aubert, C. J. Am. Chem. Soc. 2013, 135, 4576; (f) Nadeau, C.; Aly, S.; Belyk, K. J. Am. Chem. Soc. 2011, 133, 2878; (g) Jarvis, S. B. D.; Charette, A. B. Org. Lett. 2011, 13, 3830. 4. (a) Donohoe, T. J.; McRiner, A. J.; Helliwell, M.; Sheldrake, P. J. Chem. Soc., Perkin Trans. 1 2001, 1435; (b) Donohoe, T. J.; McRiner, A. J.; Sheldrake, P. Org. Lett. 2000, 2, 3861. 5. For selected reviews on the construction of a quaternary carbon centers, see: (a) Martin, S. F. Tetrahedron 1980, 36, 419; (b) Fuji, K. Chem. Rev. 1993, 93, 2037; (c) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388; (d) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591; (e) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363; (f) Christoffers, J.; Baro, A. Adv. Synth. Catal. 2005, 347, 1473; (g) Trost, B. M.; Jiang, C. Synthesis 2006, 369; (h) Bella, M.; Gasperi, T. Synthesis 2009, 1583; (i) Hawner, C.; Alexakis, A. Chem. Commun. 2010, 7295; (j) Das, J P.; Marek, I. Chem. Commun. 2011, 4593 6. (a) Reuss, R. H.; Smith, N. G.; Winters, L. J. J. Org. Chem. 1974, 39, 2027; (b) Popp, F. D.; Takeuchi, I.; Kant, J.; Hamada, Y. Chem. Commun. 1987, 1765; (c) Duarte, F F.; Popp, F. D.; Holder, A. J. J. Heterocycl. Chem. 1993, 30, 893; (d) Ichikawa, E.; Suzuki, M.; Yabu, K.; Albert, M.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 11808. 7. For selected reviews, see: (a) Albright, J. D. Tetrahedron 1983, 39, 3207; (b) Enders, D.; Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359; (c) Opatz, T. Synthesis 1941, 2009, 12. 8. (a) Zhuang, Z.; Pan, F.; Fu, J.-G.; Chen, J.-M.; Liao, W.-W. Org. Lett. 2011, 13, 6164; (b) Pan, F.; Chen, J.-M.; Zhuang, Z.; Fang, Y.-Z.; Zhang, S. X.-A.; Liao, W.W. Org. Biomol. Chem. 2012, 10, 2214; (c) Zhuang, Z.; Chen, J.-M.; Pan, F.; Liao, W.-W. Org. Lett. 2012, 14, 2354; (d) Chen, J.-M.; Fang, Y.-Z.; Wei, Z.-L.; Liao, W.W. Synthesis 1849, 2012, 44; (e) Qin, T.-Y.; Liao, W.-W.; Zhang, Y.-J.; Zhang, S. X.-A. Org. Biomol. Chem. 2013, 11, 984. 9. For recent reviews, see: (a) Liu, T.-Y.; Xie, M.; Chen, Y.-C. Chem. Soc. Rev. 2012, 41, 4101; (b) Rios, R. Catal. Sci. Technol. 2012, 2, 267; (c) Wei, Y.; Shi, M. Chem. Rev. 2013, 113, 6659. 10. CCDC 1033965 (compound 3cf) and CCDC 1034176 (compound 5 (major)) contain the supplementary crystallographic data for this Letter. 11. Asymmetric allylic alkylation of MBH adducts 2 and 1,2-dihydropyridines 1 with substituents at the 4 or 3-position did not occur in CH3CN in the presence of quinine (10 mol %) at 30 °C. 12. For details, see the Supporting information. 13. General procedure for reaction of compound 1 with MBH carbonate 2: To a dried 10 mL reaction tube under N2 atmosphere were added DABCO (20%), compound 1 (0.2 mmol), MBH carbonate 2 (1.3 equiv), and CH3CN or toluene (1 mL). Upon completion, the reaction mixture was concentrated in vacuo. The crude mixture was purified by column chromatography (silica gel, EtOAc/ Petroleum ether (60–90 °C) to provide the desired product.